The overall mission of the Experimental Therapeutics Program (ET) is to reduce the cancer burden through preclinical and early clinical drug development, to determine optimal treatment approaches, combinations and sequences, and to identify prognostic, predictive and surrogate markers of efficacy and resistance for active agents. Theme 1 is focused on targeting known driver pathways of cancer. Significant accomplishments include trial using identification of mediators of drug resistance to EGFR pathway targeted drugs and application of findings in a clinical trial. Theme 2 is focused on targeting the tumor microenvironment. Significant accomplishments include combinations of immune modulatory or antiangiogenic drugs with pathway targeted inhibitors. Theme 3 is focused on developing novel drugs and biomarkers. Significant accomplishments include establishing an algorithm for repurposing of existing drugs for cancer indications and the generation of conditionally reprogrammed cells from patients' specimens for functional and drug sensitivity screening. Under new leadership, ET is now guided by Giuseppe Giaccone, MD, PhD, former Chief of the NCI Medical Oncology Branch and a leading expert in lung cancer and experimental therapeutics, and Anton Wellstein, MD, PhD, a pharmacologist whose translational research is focused on tumor stromal interactions and mechanisms of cancer progression to metastasis. ET has 26 members, including translational and clinical researchers, representing 11 departments at Georgetown University and one at MedStar Washington Hospital Center. The Program is supported by $3M in total peer reviewed direct funding ($1.SM in NCI funding) on total funding base of $6M. From 2009 to 2012, 19 investigator-initiated trials have accrued 380 patients. In this reporting period, ET members published 339 scholarly manuscripts; 42% are intra- and/or interprogrammatic; the latter including publications with members of all three other LCCC Programs. About half of the publications (48%) involve external collaborations. ET members use all LCCC Shared Resources. The Program is organized by disease and modality groups to focus clinical research activities and prioritize clinical trials. The Cancer Center has added value to the Program by providing institutional support ($19M), recruiting leaders in the field that have enhanced ET's focus, breadth and depth (Giaccone, Atkins, Tan) and establishing the MedStar Georgetown Cancer Network to facilitate clinical research across MedStar institutions and better serve LCCC's catchment area